There is abundant evidence to suggest that the MHC Class II molecules (Ia antigens) are critically involved in the regulation of the immune response. Previous biochemical and molecular analysis has led to great insight into the functional characteristics of these molecules. The current proposal is designed to further this knowledge by analysis of the individual allelic hypervariable regions of the I-A beta chain. Initial experiments will result in the creation of transgenic mice expressing the Ab beta chain (a responder phenotype for the polypeptide antigen (T, G)-A--L) on the normally non-responder H-2s background. Should the presence of the Ab gene product result in the production of an immune response when these mice are stimulated with (T,G)-A--L, I will produce additional transgenic mouse strains, each expressing site- directed I-A beta chain mutants, in which one or more of the allelic hypervariable regions from the responder beta chain allele have been transferred into a non-responder sequence. Such transgenic mice will then be tested for immune responsiveness and expression of alloantigenic determinants, and the series of mutants can systematically test structure-function relationships.